Canadian Cardiovascular Society
Antiplatelet Guidelines
Antiplatelet Therapy for Secondary
Prevention Beyond One Year Following
ACS or PCI
Working Group: Anil Gupta MD, FRCPC, Pierre Theroux MD, FRCPC
Leadership. Knowledge. Community.
Objectives
Interpret the Canadian Cardiovascular Society Guideline
recommendations regarding the use of antiplatelet
therapy for patients with stable coronary artery disease.
Distinguish when it is appropriate to continue or
discontinue dual antiplatelet therapy 1 year post event.
Evaluate the evidence supporting the use of antiplatelet
agents in patients with stable coronary artery disease.
© 2011 - TIGC
Mary
Mary is a 72 year-old retired teacher who suffered
a NSTEMI three years ago.
She was managed medically and made an uneventful
recovery.
Since her event she remains asymptomatic and has
no significant comorbidity.
© 2011 - TIGC
Mary
Which of the following are appropriate antiplatelet
regimens for Mary?
A. ASA 81 mg OD
B.
Clopidogrel 75 mg daily
C.
ASA 81 mg + Clopidogrel 75 mg daily
D. Any of the above
© 2011 - TIGC
Benefit of antiplatelet therapy
Antithrombotic trialists collaboration
ARR 3.5 % 13.5% vs 17.0%
NNT 29
© 2011 - TIGC
Antithrombotic Trialists, BMJ 2002; 324: 71-86.
Absolute benefit of ASA in secondary prevention
Baigent C, Blackwell L, Collins R, et al. Lancet 2009;373:1849-60.
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Stable CAD
ASA VS CLOPIDOGREL
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CAPRIE
Study design
Multicentre, prospective, blinded
Study population
19,185 patients with atherosclerotic
vascular disease
Qualifying conditions Ischemic stroke (>1 week and <6 months)
Myocardial infarction (MI) (<35 days)
Peripheral Vascular disease
Study drugs
Clopidogrel 75 mg once daily
Aspirin 325 mg once daily
Primary endpoint
MI, ischemic stroke, or vascular death
Treatment duration
Up to 3 years (mean 1.6 year)
Investigational sites
384 in 16 countries
CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
© 2011 - TIGC
CAPRIE results
Relative Risk Reduction* by qualifying entry criteria
7.3
IS (n=6431)
-3.7
MI (n=6302)
23.8
PAD (n=6452)
8.7
20
10
ASA better
0
Total (n=1918)
10
20
30
40
Clopidogrel better
*Cluster of IS, MI, or vascular death.
CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
CAPRIE bleeding
% of patients with events
Aspirin (325 mg/d) Clopidogrel (75 mg/d)
Intracranial hemorrhage
0.49
0.35
Gastrointestinal bleeding
2.66 *
1.99
Severe bleeding
1.55
1.38
Any bleeding
9.28
9.27
*p<0.05
CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
Stable CAD
DUAL ANTIPLATELET THERAPY
VS
ASA MONOTHERAPY
© 2011 - TIGC
CHARISMA
Study design
Clopidogrel
75 mg/day
(n=7802)
Patients age ≥ 45
years at high risk of
atherothrombotic
events
R
(n=15603)
Low dose ASA 75162 mg/day
Double-blind treatment up to 1040
primary efficacy events*
Low dose ASA 75162 mg/day
Placebo
1 tablet/day
(n=7801)
1-month
visit
3-month
visit
Visits every 6 months
* MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death;
event-driven trial
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
Final visit
(Fixed study
end date)
CHARISMA
Inclusion criteria
Patients aged ≥45 years
with
at least one of the following:
1) Documented coronary disease
and/or
2) Documented cerebrovascular disease
and/or
3) Documented symptomatic PAD
and/or
4) Two major or one major and two minor or three minor risk
factors
Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.
Primary efficacy results (MI/troke/CV death)
by pre-specified entry category
Population
RR (95% CI)
Prior CV event
p value
0.88 (0.77, 0.998) 0.046
(n=12153)
Risk Factors Only
1.20 (0.91, 1.59)
0.20
0.93 (0.83, 1.05)
0.22
(n=3284)
Overall Population*
(n=15603)
0.4
0.6
0.8
Clopidogrel + ASA
Better
1.2
1.4
1.6
Placebo + ASA
Better
* A statistical test for interaction showed marginally significant heterogeneity
(p=0.045) in treatment response for the pre-specified subgroups of symptomatic
and asymptomatic patients
AT=Atherothrombosis
Adapted from Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.
Stable CAD
LONG TERM ANTIPLATELET THERAPY
IN PATIENTS WITH PCI
© 2011 - TIGC
Stent thrombosis
Stent thrombosis occurs following 0.5%-2% of stent placements.
Major safety concern with rates of mortality as high as 45%
Occurs most frequently in the first month after stent
implantation (subacute).
Cases of late (30 days to 1 year) and very late (> 1 year)
stent thrombosis occur particularly in DES recipients.
© 2011 - TIGC
Stent thrombosis
Predictors of late stent thrombosis
Drug Eluting Stent
Stenting of small vessels
Decreased left ventricular
function
Presence of multiple lesions
Advanced age
Long segments implanted with
overlapping stents
Diabetes
Stenting of ostial bifurcation
lesions
ACS
Renal failure
Suboptimal stent deployment
© 2011 - TIGC
Stent thrombosis
Drug Eluting vs Bare Metal
Median time to stent thrombosis
20
p = 0.0003
p = 0.0052
p = 0.04
16
Months
12
8
4
0
DES BMS
SES BMS
Bavry AA, et al. Am J Med. 2006;119:1056-61.
PES BMS
Incidence of very late stent thrombosis
> 1 Year
Per 1,000 pts
7
6
RR = 5.7
p = 0.049
RR = 5.0
p = 0.02
5
p = 0.22
4
3
2
1
0
DES BMS
SES BMS
Bavry AA, et al. Am J Med. 2006;119:1056-61.
PES BMS
Discontinuation of Thienopyridine therapy
after DES implantation
MI patients who stopped
thienopyridine therapy by 30 days
post-DES were more likely to die
during the next 11 months
15
Mortality (%)
Continued
Discontinued
Adjusted hazard ratio
9.0; 95% CI = 1.3 to
60.6
10
P<0.001
5
0
0
1
2
3
4
5
6
7
Months
Spertus JA, et al. Circulation. 2006;113:2803–2809.
8
9
10
11
12
BASKET LATE
Late thrombotic events following Thienopyridine discontinuation
Cardiac death or MI
P=0.01
MI
P=0.04
6
6
4.9
4.1
4
2
Percentage (%)
Percentage (%)
4
1.3
0
2
0
Drug-eluting
stents
Drug-eluting
stents
Pfisterer ME, et al. J Am Coll Cardiol. 2006;48(12)
1.3
Bare metal stents
Clopidogrel use and long-term
outcomes after BMS or DES stenting
Adjusted cumulative rates of composite of death or MI using the 6-month
landmark analysis
Composite of Death or MI
8
Cumulative Incidence (%)
DES
With Clopidogrel
6
Without Clopidogrel
4
BMS
With Clopidogrel
2
Without Clopidogrel
0
6
12
Eisenstein EL, et al. JAMA. 2007;297(2):159-68.
18
Months
24
REAL-LATE/ZEST-LATE
Definite Stent Thrombosis
Days from Randomization
Park SJ, Park DW, et al. N Engl J Med 2010;362
Cumulative Incidence (%)
Cumulative Incidence (%)
• 2701 patients who had received drug eluting stents
• Free of major adverse cardiac or cerebrovascular events and
major bleeding for a period of at least 12 months
• Randomized open label to receive clopidogrel plus aspirin or
aspirin alone
Days from Randomization
© 2011 - TIGC
24
®
Antiplatelet therapy for secondary prevention
beyond 1 year following acute coronary syndrome
or percutaneous coronary intervention
1.
2.
3.
4.
5.
For all patients with ACS who survive to hospital discharge, indefinite
therapy with low-dose ASA (75-162 mg daily) is recommended (Class I,
Level A).
For patients allergic to or intolerant of ASA, indefinite therapy with
clopidogrel 75 mg daily is recommended (Class IIa, Level B).
Dual antiplatelet therapy with ASA 75-162 mg daily and clopidogrel 75 mg
daily may be considered beyond 1 year in patients with ACS (see post-ACS
recommendations) who are medically managed provided the risk of
bleeding is low (Class IIb, Level C).
For all post-PCI patients, indefinite therapy with ASA 75-162 mg daily is
recommended, regardless of type of stent (Class I, Level A).
Dual antiplatelet therapy with ASA 75-162 mg daily and clopidogrel 75 mg
daily may be considered beyond 1 year in patients with ACS who receive a
BMS or DES provided their risk of bleeding is low (Class IIb, Level C).
25
®
Antiplatelet therapy for secondary
prevention beyond 1 year
following ACS or PCI
High-risk Mary
What if Mary has additional risk factors for recurrent thrombosis
including:
Drug eluting stent implantation
Diabetes
Other prior vascular events including TIA?
© 2011 - TIGC
CAPRIE
Clopidogrel vs ASA in multi-bed disease
15
Annual event rate (%)
10.74%
10
8.35%
5
0
Clopidogrel
ASA
Events = ischemic stroke, MI or vascular death
Lancet 1996; 348(9038):1329-39.
CAPRIE
Risk reduction in patients with diabetes
Annual event rate (%)
25
Clopidogrel
20
21.5%
17.7%
1
5
10
ASA
17.7%
15.6%
11.8%
12.7%
5
0
Non diabetic
All diabetic patients
With insulin
Events = ischemic stroke, MI , vascular death, hospitalization for ischemic events/bleeding
Overall benefit p=0.032; multivariate analysis
Bhatt DL et al. J Am Coll Cardiol 2000;35 (Suppl A):409
CHARISMA
Primary Endpoint (MI/Stroke/CV Death) in patients
with previous MI, IS or PAD*
N=9,478
“CAPRIE-like Cohort”
8.8%
Primary Outcome Event Rate (%)
10
7.3%
Placebo + ASA
Clopidogrel + ASA
8
6
4
RRR: 17.1 % (95% CI: 4.4%, 28.1%)
P=0.01
2
0
0
* Post hoc analysis.
6
12
18
24
30
Months Since Randomization
Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.
High-risk Mary
Mary’s additional risk factors suggest more aggressive
antiplatelet therapy should be considered.
As long as her bleeding risk is low, she may be advised
to continue dual antiplatelet therapy with ASA 81 mg +
clopidogrel 75 mg.
© 2011 - TIGC
31
®
Antiplatelet therapy for secondary
prevention beyond 1 year following
ACS or PCI
Prasugrel or Ticagrelor?
No long term secondary prevention studies are available
for these agents.
Prasugrel should be avoided in patients with:
Age > 75
Weight < 60 kg
Prior cerebrovascular disease
© 2011 - TIGC
© 2011 - TIGC